The 4,5,6,7-tetrahydrobenzothiazole compounds of general formula (A):
also referred to as 2-amino-6-(R1,R2)amino-4,5,6,7-tetrahydrobenzothiazoles, wherein R1 is hydrogen, alkyl or aralkyl and R2 is hydrogen, are known as useful pharmacological agents.
Among these compounds, the S-enantiomer of 2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole, known as pramipexole, which is a commercial product with dopamine D2 agonist activity, must be highlighted. This product is marketed in dihydrochloride form for the treatment of Parkinson's disease, schizophrenia or hypertension, under different trademarks, such as Mirapexin® for example.
2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole is described for the first time in EP 186 087, in addition to other related compounds and their use. Within the family of patents to which it belongs there are other documents, such as U.S. Pat. No. 4,731,374 and its divisional patents U.S. Pat. No. 4,843,086 and U.S. Pat. No. 4,886,812; ES 550235 and its divisional patents ES 556873, ES 556874 and ES 556875, which also describe analogous compounds and processes of obtaining them.
The compounds of general formula (A) have an asymmetrical carbon atom and can exist either as pure enantiomeric forms or as mixtures thereof. However the pharmacological activity of said compounds is much greater in one of its enantiomeric forms, as occurs for example with pramipexole, which is marketed as the substantially pure S(−) isomer given that the dopaminergic activity of said isomer is two times greater than that of the R(+) isomer. Though the previously mentioned state of the art claims the possible enantiomers, it only allows the preparation of the racemate as it is understood from the described examples.
The first bibliographic reference in which a process for obtaining the different enantiomers of 2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole is described is a publication of Schneider and Mierau in the J. Med. Chem., 1987, 30, 494. In said publication, pramipexole is not directly resolved from the racemic mixture but from a precursor of it, specifically compound (A) wherein R1═R2═H, which is reacted with L(+)-tartaric acid acting as a resolving agent. After said resolution, the optically active pramipexole is prepared by means of a two-step propylation of the pure enantiomer of the diaminated precursor, comprising reaction with propionic anhydride followed by reduction of the propionylated intermediate. The rotatory power value described in this publication for pramipexole dihydrochloride is αD=−67.2° (c=1 CH3OH).
In turn, ES 2187249 describes obtaining the compound of formula (A) enriched in the desired enantiomer by means of a synthetic route such as the one described below:

This process comprises the selective monobromination of cyclohexanedione (D) in an alcoholic solvent to give the compound of formula (E) wherein R3 and R4 are the same or each one represents an 1-4 carbon atom alkoxy group, or together form a C2-C5 alkylenedioxy group or an oxo-group; a condensation with a thiourea gives a compound of formula (F) and finally, a reaction of said compound (F) with a suitable amine under reductive amination conditions. This method allows producing pramipexole substantially enriched in the desired S(−) enantiomer by using a chiral catalyst for the reductive amination to propylamine or by using a chiral amine convertible to propylamine as a reagent in reductive amination.
Example 6 of said patent also describes a process for the resolution of racemic pramipexole base using L(+)-tartaric acid to obtain pramipexole tartrate and subsequently pramipexole dihydrochloride. The obtained results however reflect a rotatory power value of only αD=−48.8° (c=1, MeOH), which does not correspond to an optically pure product in view of the mentioned prior art, but rather to a mixture of (S)-enantiomer-enriched enantiomers.
Patent application WO 02/22591 describes a process for the resolution of pramipexole, consisting of, given the dibasic character of pramipexole, forming an intermediate mono-salt of general formula:
wherein Y is the monovalent anion derivative of an acid selected from hydrochloric, hydrobromic, hydriodic, nitric, benzoic, acetic, methanesulfonic, ethanesulfonic, trifluoromethanesulfonic, benzenesulfonic and paratoluenesulfonic acid, and then forming a di-salt of general formula:
wherein Y is as hereinbefore defined and Z is the anion derivative of an optically active acid selected from L-tartaric, di-p-toluyl-D-tartaric and dibenzoyl-D-tartaric acid. The “mixed” diastereoisomeric salts are split by crystallization in the described process. The rotatory power values obtained in this publication for pramipexole dihydrochloride are αD=−66.5°, C=1, CH3OH (at the very best, see Example 1-d).
In this case, even though a product with a greater enantiomeric purity in the pramipexole (S) isomer is obtained, it is necessary to carry out several steps which complicate and prolong the process, such as the initial formation of a mono-salt of the product and its subsequent isolation then followed by a second step comprising the addition of an optically active acid, and finally one or more additional steps are necessary for obtaining by diastereoselective recrystallization one of the diastereomeric salts which provides the suitable isomer by subsequent release.
On the other hand, though the obtained rotatory power values are more satisfactory than in the prior art, they do not correspond to a product complying with the high optical purity requirements necessary for products with pharmacological activity, such as pramipexole.
Therefore despite the existence of processes allowing the resolution of racemic pramipexole by fractionated crystallization using classic resolving agents such as chiral acids, such as tartaric, di-p-toluyl-D-tartaric, mandelic acid, etc. . . . , in organic solvents, these lead to compounds with low optical purity and little reproducibility. This has caused there to be a serious need to develop alternative processes which allow obtaining enantiomers of a high optical purity.